This project is designed to investigate interactions between acute stress and drugs of abuse, and to compare stress-drug interactions in men and women. The studies are based on preclinical research indicating that stress, through various neural and endocrine mechanisms, increases drug self-administration and alters acute responses to drugs. The studies also address clinical observations that stress increases drug use and relapse to drug use in drug-dependent individuals. The physiological and psychological effects of both stress and drugs depend on the sex, hormonal state, and drug history of the individual. The proposed laboratory studies will investigate how acute stress alters the acute responses to drugs or the propensity to use drugs. First, we propose to characterize the time course of subjective, physiological and hormonal responses to acute social stress in several groups, including men and women, women at different phases of the menstrual cycle and male smokers vs nonsmokers. Second, we will investigate the effects of acute stress on responses to two stimulant drugs, methamphetamine and nicotine, administered at varying times after (or before) stress. Our preliminary data suggest that stress dampens the stimulant-like subjective effects of drugs, but this effect is likely to depend on the interval between the stress and ingestion of the drug. Third, we will investigate the interaction between stress and methamphetamine or nicotine in men vs women, smokers vs nonsmokers, and in women at different phases of the menstrual cycle phase. Based on previous studies with humans and non-humans, we hypothesize that the psychological effects of stress will be greater in women than men, in non-smokers than smokers, and during the luteal phase compared to the follicular phase in women. Finally, we propose to investigate the effects of stress on smoking behavior and on reactions to smoking-related cues in regular cigarette smokers. Taken together, these studies will provide a critical link between preclinical findings and clinical observations, to elucidate how stress increases drug use. The results of these studies will improve our understanding of mechanisms by which stress increases drug use, and could lead to improved methods for preventing and treating stress-related drug use. [unreadable] [unreadable]